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This study investigates how local inhibition of DNA double-strand break (DSB) formation, mediated by the Tel1 kinase in yeast, reshapes the genome-wide DSB landscape. By developing a quantitative simulation framework, the authors demonstrate that innate chromosome-specific patterns combined with interference generate complex population-level redistribution of breaks. The research identifies the spatial range of this interference and confirms its dependence on Tel1 recruitment via Xrs2 and kinase activity.

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Abstract

Genetic diversity within sexually reproducing species arises via the formation and repair of programmed DNA double-strand breaks (DSBs) created by the evolutionarily conserved topoisomerase-like enzyme, Spo11. Because DSBs threaten genome stability, their formation is tightly regulated in both space and time. In S. cerevisiae, Tel1, the orthologue of mammalian Ataxia Telangiectasia Mutated (ATM) kinase, suppresses nearby DSB formation through local inhibition known as DSB interference. However, whether such local inhibition reshapes the genome-wide DSB landscape remains unclear. Here, we develop a quantitative simulation framework to model how Tel1-mediated feedback shapes Spo11-DSB formation across the yeast genome. We demonstrate that innate chromosome-specific DSB patterns, when combined with interference, generate complex, population-level redistribution of DSBs. We define the spatial range over which interference propagates and provide evidence that this regulatory mechanism requires Tel1 recruitment to DSBs via Xrs2 and Tel1 kinase activity. Although the pro-DSB factor Rec114 contributes to DSB regulation, mutation of potential Rec114 phosphorylation sites indicates that it is not an essential target of Tel1. Together, these findings demonstrate how localised negative feedback can drive broad-scale, emergent patterning of a fundamental genome-modifying process, with the potential in meiosis to influence recombination initiation and, consequently, genetic variation across generations.

Key findings

  • Tel1-mediated local inhibition (DSB interference) causes a complex, population-level redistribution of Spo11-DSBs across the yeast genome.
  • The regulatory mechanism requires the recruitment of Tel1 to DSBs through Xrs2 and subsequent Tel1 kinase activity.
  • While Rec114 contributes to regulation, specific phosphorylation sites on it are not strictly required for the observed interference effects.

Keywords

Homologous recombinationMeiosisCell biologyDNAGeneticsChromosome segregation

Identifiers

DOI
10.64898/2026.02.23.706156
Journal
bioRxiv (Cold Spring Harbor Laboratory)
Year
2026